SUMMARY/ABSTRACT At least 80 autoimmune diseases (ADs) have been identified to date, affecting more than 23.5 million Americans. For the majority of ADs, there is no clear method of diagnosis. Early intervention is key to controlling the progression of disease, thus delays in diagnosis lead to higher disease burdens for patients and increased costs for treatment. Current diagnostic methods are complex, non-standardized and frequently inconclusive. Systemic sclerosis (SSc) is one of the most disabling autoimmune rheumatic disorders. SSc is a rare disease, affecting between 40,000 to 165,000 people in the United States, and is three to four times more common in women than men. Uncertainty in prevalence derives from the complexity of a disease characterized by both organ specific and systemic manifestations. It is a multisystem disease characterized by widespread vascular dysfunction and progressive fibrosis of the skin and internal organs, and diagnosis most often occurs only after significant and irreversible tissue and organ damage. Thus, there is an urgent unmet need to develop a simple, rapid test that can lead to early diagnosis of systemic sclerosis. ADs are characterized by loss of self-tolerance by the immune system and the production of abnormal levels of autoantibodies. These autoantibodies, whether pathological or not, are the serological markers of autoimmunity. It is now clear that the heterogenous and overlapping nature of AD makes it unlikely that any single autoantibody will be unique and diagnostic for a particular disease. A promising approach for developing new diagnostics therefore relies on the identification of an autoantibody ?signature? that, when taken together, could unambiguously diagnose a particular disease. We propose to screen random peptides to develop a novel, multiplex peptide array that can be used by any clinical laboratory to diagnose systemic sclerosis. The use of random peptides ensures that we are un- constrained by pre-existing knowledge about which antibodies are enriched or significant in SSc. Our technology will only require that a signature group of antibodies is reproducibly present in the blood of SSc patients, but not in healthy patients or those with other ADs. Phage display biopanning of SSc patient immunoglobulin using a random peptide library followed by next generation sequencing will be unbiased and exhaustive. We are not concerned with the identity of antigens or autoantibodies; we are instead focused on identifying a unique peptide signature that can be used to unambiguously diagnose SSc. Our peptide-based diagnostic array will be familiar to end users in clinical labs and will significantly shorten the time to diagnosis, allowing for immediate treatment and monitoring.